Cholangiocarcinoma (CCA) diagnosis requires a combination of methods, including imaging, tumor markers, and biopsy/cytology.
While biopsy is an invasive procedure, the typically used tumor markers carbohydrate antigen (CA)19.9 and carcinoembryonic antigen (CEA) are nonspecific, and imaging is suboptimal in the differential diagnosis of CCA and hepatocellular carcinoma (HCC), underscoring the need for accurate noninvasive diagnostic tests and biomarkers, which is particularly important for early diagnosis in high-risk individuals with primary sclerosing cholangitis (PSC).
At the 2024 Cholangiocarcinoma Foundation Annual Conference, Pedro M. Rodrigues, PhD, outlined several novel noninvasive strategies for biomarker discovery that may be utilized for early and differential diagnosis of CCA, PSC-CCA, intrahepatic CCA (iCCA) versus HCC, as well as to predict which patients with PSC will develop CCA.
Dr Rodrigues noted that CA19.9 and CEA are not ideal diagnostic markers since they are enormously elevated only in advanced disease and are not expressed in 10% of the population. However, CA19.9 may have independent prognostic value in CCA.
Liquid biopsy has emerged as a noninvasive strategy for discovering biomarkers. It involves isolating and analyzing cell-derived material (eg, DNA, RNA, circulating tumor cells, and extracellular vesicles [EVs]) from blood or other body fluids.
Dr Rodrigues described his work on proteomic profiling of serum EVs, which are small membrane spheres secreted by cells into the extracellular milieu and can be detected in biological fluids (eg, blood, urine, bile, saliva, milk). They are composed of proteins and metabolites, nucleic acids, and lipids. There are different types of EVs based on origin, molecular composition, and biological function, making them helpful in detecting different cell entities.
Dr Rodrigues’s group used high-throughput proteomics of serum EVs isolated from patients with PSC alone, concomitant PSC-CCA, pan-CCA (ie, CCAs of all etiologies), and HCC to identify diagnostic biomarkers and for the differential diagnosis of iCCA and HCC, which were cross-validated by ELISA using the total serum.
Using this approach, C-reactive protein (CRP) plus ferritin light chain (FRIL) plus FIBRINOGEN was identified as biomarkers for the early diagnosis of PSC-CCA (area under the curve [AUC] = 0.90), CRP plus FRIL for the diagnosis of early CCA (AUC = 0.94), and CRP plus fibrinogen-like protein 1 to distinguish between iCCA and HCC (AUC = 0.96). CRP plus FIBRINOGEN plus FRIL plus polymeric immunoglobulin receptor showed predictive capacity for CCA development in individuals with PSC (AUC = 0.91).
Dr Rodrigues also shared his work using the serum metabolomics platform to identify changes in serum metabolite concentrations, allowing for differential diagnosis of iCCA, HCC, and PSC and early diagnosis of these conditions.
Using serum metabolomics, a combination of 6 lipid metabolites was identified that could differentiate between iCCA and HCC (AUC = 0.90/0.98). Also, a differential metabolic profile of 10 metabolites was identified (AUC = 0.98/0.83), allowing for the prediction and early detection of CCA in patients with PSC.
Dr Rodrigues concluded that novel noninvasive liquid biopsy tools are identifying biomarkers of diagnostic and prognostic value for patients with CCA, and international prospective validations are ongoing to confirm these results so that personalized medicine may be applied in clinical practice in the future.1
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